A new study by researchers at the Wistar Institute demonstrates how key features on the surface of HIV-infected cells help the disease evade detection by the immune system. The researchers discovered that HIV-infected cells are using a type of sugar molecule called sialic acid to be disguised and evade natural killer immune surveillance. Their findings also reveal an approach that stops HIV-infected cells and leaves healthy cells unharmed.

Their findings are published in the journal PLOS Pathogens, in a paper titled, “Siglec-9 Defines and Restrains a Natural Killer Subpopulation Highly Cytotoxic to HIV-infected Cells.”

“We identified a glyco-immune checkpoint interaction as a novel mechanism that allows HIV-infected cells to evade immune surveillance,” explained Mohamed Abdel-Mohsen, PhD, assistant professor in the Vaccine & Immunotherapy Center at the Wistar Institute and co-author. “And we developed a novel approach that selectively targets these interactions on the surface of these infected cells.”

The researchers looked at a type of sugar molecule called sialic acid on the surface of HIV-infected cells. These sugars bind on the surface of disease-fighting “natural killer” immune cells. “We thought, ‘is it possible that these HIV-infected cells are using this interaction— covering themselves with these sugars to evade the natural killer immune surveillance?’” said Abdel-Mohsen.

The Abdel-Mohsen lab discovered that the infected cells can take advantage of this inhibitory connection to evade immune surveillance. They then observed whether they could manipulate this connection. The researchers tried different approaches before they discovered the approach of developing a sialidase conjugate linked to HIV antibodies. This antibody-sialidase conjugate only targeted sialic acid on HIV cells. Using this approach allowed the killer immune cells to target HIV-infected cells while leaving healthy unharmed.

“The killer cells become a super killer for the HIV-infected cells and they now attack them in a selective manner,” said Abdel-Mohsen. “The discovery could be a missing link in the “shock and kill” approach to HIV treatment that has been a focus of research for the past several years,” he added. This two-step process involves first “shocking” the HIV out of latency so it can be detected, and then stimulating the immune system to “kill” the virus once and for all. However, while effective methods have been discovered to reverse latency, scientists haven’t yet found a way to make HIV-infected cells more killable once reactivated. “We may have the shock, but we don’t have yet the kill,” Abdel-Mohsen said. “Our method actually increases the susceptibility of HIV-infected cells to killing, which is one of the top unmet needs in the HIV field.”

First author Samson Adeniji, PhD, a postdoctoral fellow at Wistar, noted that the team’s approach could be tested in combination with broadly neutralizing antibody therapies currently being studied in clinical trials. “By combining approaches, we could turn these immune cells from a cop into a kind of Robocop,” he said.

The researchers are looking to move forward with animal studies to test their findings in vivo. “HIV-infected cells are likely evading immune surveillance through many potential glyco-immune checkpoints,” Abdel-Mohsen said. “We are investigating other mechanisms and how to break them.”